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Jaspinder Sra,
MD*,
Allen B. Repp,
KEYWORDS
Hyponatremia Osmotic demyelination Antidiuretic hormone
Total body water
DEFINITION
1. What is hyponatremia?
Hyponatremia is defined as a serum sodium concentration less than 135 mEq/L. In the
past, high serum lipid or serum protein levels could result in erroneously low serum
Department of Medicine, Division of Primary Care Internal Medicine, University of Vermont
College of Medicine, Fletcher Allen Health Care, 111 Colchester Avenue, Burlington, VT
05401, USA
* Corresponding author.
E-mail address: jaspindersra@gmail.com
Hosp Med Clin 1 (2012) e199e208
doi:10.1016/j.ehmc.2012.03.007
2211-5943/12/$ see front matter 2012 Elsevier Inc. All rights reserved.
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Normal Osmolality
High Osmolality
Nonelectrolyte irrigation
solutions
Glycine
Sorbitol (TURP, hysterectomy,
laparoscopic surgery)
Marked hyperglycemia
Serum sodium decreases 1.6
mEq/L for every increase of
100 mg/dL in glucose
SIADH
Pseudohyponatremia
Largely eliminated by
modern laboratory assays
Hormonal changes
Adrenal Insufficiency
Hypothyroidism
hCG during pregnancy
(mild osmotic resetting)
Exercise induced
Renal failure
Primary polydipsia
Low dietary solute intake
Abbreviations: BUN, blood urea nitrogen; hCG, human chorionic gonadotropin; SIADH, syndrome
of inappropriate antidiuretic hormone hypersecretion; TURP, transurethral resection of the
prostate.
Data from Refs.811
Hyponatremia
distinctions are particularly important because each of these clinical situations is associated with specific disease states and respond to different therapies (Table 2).
3. What is the pathophysiology of hyponatremia?
To understand the pathophysiology of hyponatremia, one must understand how the
body maintains serum osmolality and effective arterial blood volume (EABV). Although
these 2 processes are closely related, they are regulated by distinct physiologic
pathways.
EABV is primarily controlled by carotid and aortic baroreceptors, which regulate
blood pressure through changes in vascular tone, and the juxtaglomerular apparatus
in the kidney, which regulates the renin-angiotensin-aldosterone system (RAAS). Activation of the RAAS causes vasoconstriction through the effects of angiotensin on
vascular smooth muscles and sodium retention through the actions of aldosterone.
Serum osmolality is maintained by regulation of the intake and excretion of free
water. The former is controlled by the thirst mechanism and the latter by the actions
of antidiuretic hormone (ADH) on the kidney, which is the primary hormone responsible for maintaining osmolality. ADH is secreted by the posterior pituitary and acts
on the V2 receptors in the renal collecting tubules to increase free water reabsorption.
Under normal physiologic conditions, ADH secretion is tightly controlled by changes in
serum osmolality: below a Sosm of approximately 280 mOsm/kg, ADH is completely
suppressed; above that value, ADH secretion increases rapidly. Thus, when the Sosm
is low, ADH secretion is low, and the kidney excretes maximally dilute urine (50100
mOsm/kg). Conversely, when the Sosm increases, ADH secretion increases proportionally, which causes the kidney to make concentrated urine and resorb free water,
Table 2
Classification of hypotonic hyponatremia by volume status
Volume Status TBS/TBW Urine Na <20 mEq/L
Hypovolemic
YY/Y
Euvolemic
4/[
Hypervolemic
[/[[
GI losses (vomiting,
diarrhea)
Insensible losses
(pancreatitis,
burns, sweating )
Comments
Often associated
Diuretics
hyperuricemia
Mineralocorticoid
due to shared
deficiency
activation of
Osmotic diuresis
proximal tubular
Ketonuria
Na/Cl transport
Cerebral salt wasting
and uric acid
transport
Hypothyroidism
Glucocorticoid
deficiency
Pain, stress
SIADH
Drugs
CHF, decreased
Acute or chronic
cardiac output
renal failure
Cirrhosis, arteriolar Concomitant
vasodilatation
diuretic therapy
Nephrotic syndrome
ADH is an ACTH
secretagogue
In CHF, degree of
hyponatremia has
prognostic value
Abbreviations: ACTH, corticotropin; ADH, antidiuretic hormone; CHF, congestive heart failure; GI,
gastrointestinal; TBS, total body salt; TBW, total body water.
Data from Refs.811
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thereby returning free water to the circulation. With maximal ADH secretion the urine
can be concentrated up to 900 to 1200 mOsm/kg.
Although normally insensitive to changes in EABV, ADH secretion will occur when
there is a marked decrease in EABV, as may occur with blood loss, dehydration, or
advanced cirrhosis or heart failure. This process explains why ADH may be secreted
in hypovolemic states, even when the Sosm is below normal. In these settings the
RAAS system is also activated, and through the effects of aldosterone the kidney is
sodium avid, which manifests as urine sodium concentration generally less than 40
mEq/L. Hypovolemic hyponatremia is typically transient as volume repletion leads
to suppression of ADH and the RAAS.
In euvolemic hyponatremia, ADH secretion is triggered by processes unrelated to
Sosm or EABV. This secretion may occur in response to many stimuli including
pain, nausea, pulmonary infections, or medications. ADH may also be ectopically
produced by several malignancies such as small-cell lung cancer. Similar effects
may be observed in hypothyroidism and adrenal insufficiency. In the setting of euvolemia aldosterone levels are low, and the urine sodium concentration is generally
greater than 40 mEq/L.
Paradoxically, most hypervolemic states, such as heart failure, cirrhosis, and the
nephrotic syndrome, are characterized by total body volume overload accompanied
by low EABV. As in hypovolemic hyponatremia, low EABV triggers both ADH secretion
and the RAAS. This process results in water and sodium retention, with retention of
water greater than that of salt. Therefore, urine sodium is usually less than 20 mEq/L
unless there is concomitant diuretic therapy or impairment in renal function. Because
the underlying disease states are chronic, the stimulus for ADH secretion and RAAS
activation is persistent.
EPIDEMIOLOGY
Hyponatremia
edema and symptoms develop when these compensatory mechanisms are overcome
by a rapid decrease in osmolality. Early symptoms include malaise, headache,
nausea, and vomiting. Seizures, brainstem herniation, respiratory arrest, coma, and
death can occur: acute symptomatic hyponatremia is a medical emergency.
In chronic hyponatremia, symptoms are usually lacking in patients with sodium
levels of more than 125 mEq/L, but when present, may include subtle defects in
gait and cognition that improve with correction of hyponatremia.5 Once serum sodium
falls below 125 mEq/L, neurologic symptoms become more likely and may include
fatigue, gait abnormalities, memory impairment, vomiting, nausea, confusion, and
(rarely) seizures.
2. What are the key elements of the clinical history that should be evaluated in patients
with hyponatremia?
A careful review of recent events, medical history, medication changes, and social and
psychiatric history is essential in ascertaining the cause of hyponatremia. Table 3
details key historical elements in hyponatremia.
Table 3
Key historical elements in hyponatremia
Category
Element
Current hospitalization
Recent surgery/trauma/pain
IVF (administration of hypotonic fluids)
Irrigation with glycine (TURP, laparoscopy)
Medical history
Current pregnancy
Recent vomiting, diarrhea
Diabetes mellitus, hyperglycemia
Heart failure, edema, dyspnea
Pulmonary disease or symptoms
Renal disease
Cirrhosis
Hypothyroidism
Adrenal insufficiency
Central nervous system disease or insult
Medicines
Medication changes
Diuretics
ACE inhibitors
Medications associated with SIADH (see Box 1)
Social history
Psychiatric history
3. What signs, symptoms, and laboratory data are most accurate in assessing volume
status in a patient with hyponatremia?
Although assessment of volume status is key to the classification of hyponatremia,
there is no single sign or laboratory result that reliably indicates volume status. Much
of the literature in assessing volume status stems from evaluation of patients with dyspnea or suspected heart failure. In this population, the presence of dyspnea on exertion,
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rales on lung examination, and elevated brain natriuretic peptide are highly sensitive but
not specific for hypervolemia, whereas paroxysmal nocturnal dyspnea, systolic hypotension, jugular venous distention, third or fourth heart sounds, and the presence of
ascites are more specific but not as senstive.6,7 Although peripheral edema suggests
hypervolemia and argues against hypovolemic hyponatremia, its sensitivity and specificity for volume overload are not exceptionally high (see Table 2).7
DIAGNOSIS
MANAGEMENT
Hyponatremia
Box 1
Common inpatient medications associated with syndrome of inappropriate antidiuretic
hormone hypersecretion
Selective serotonin reuptake inhibitors
Tricyclic antidepressants
Carbamazepine
Opiates
Nonsteroidal anti-inflammatory medications
Haloperidol
Nicotine
Data from Refs.811
Value
Sodium deficit
Equation
(total body water) (desired serum sodium actual serum
sodium)
Total body water 5 0.5 weight (kg) for women, and 0.6 weight (kg) for men
154
Lactate Ringer
130
77
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Hyponatremia
mediators. It is postulated that these insults are the basis for ODS. As hyponatremia is
reversed, patients may initially improve, but over the next few days they develop
progressive neurologic deficits, from dysphagia, dysarthria, and diplopia to paraparesis, quadriparesis, or even locked-in syndrome. The lesions in ODS typically affect the
pons (historically ODS was known as central pontine myelinolysis) but other regions
can also be affected, notably the thalamus, cerebellum, and the putamen.14
ODS is best prevented by slow correction of chronic hyponatremia, no more than 12
mEq/L within the first 24 hours and less than 18 mEq/L within the first 48 hours. Once
ODS has set in, relowering of the serum sodium concentration may prevent or reduce
further loss of neurologic function.14
GUIDELINES AND STATEMENTS
1. Hawkins RC. Age and gender as risk factors for hyponatremia and hypernatremia. Clin Chim Acta 2003;337:16972.
2. Cyr PL, Slawsky KA, Olchanski N, et al. Effect of serum sodium concentration and
tolvaptan treatment on length of hospitalization in patients with heart failure. Am J
Health Syst Pharm 2011;68(4):32833.
3. Waikar SS, Mount DB, Curhan G. Mortality after hospitalization with mild,
moderate, and severe hyponatremia. Am J Med 2009;122(9):857.
4. Strange K. Regulation of solute and water balance and cell volume in the central
nervous system. J Am Soc Nephrol 1992;3(1):12.
5. Renneboog B, Musch W, Vandemergel X, et al. Mild chronic hyponatremia is
associated with falls, unsteadiness, and attention deficits. Am J Med 2006;
119(1):71.e18.
6. Peacock WF, Soto KM. Current techniques of fluid status assessment. In:
Ronco C, Costanzo MR, Bellomo R, et al, editors. Fluid overload: diagnosis
and management (contrib nephrol), vol. 164. Basel (Switzerland): Karger
Publishers; 2010. p. 12842.
7. Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the
emergency department have congestive heart failure? JAMA 2005;294(15):
194456.
8. Yeates KE, Singer M, Morton AR. Salt and water: a simple approach to hyponatremia. CMAJ 2004;170(3):3659.
9. Mount DB. Fluid and electrolyte disturbances. In: Longo DL, Fauci AS, Kasper DL,
et al, editors. Harrisons principles of internal medicine. 18th edition. New York:
McGraw-Hill; 2012. Chapter 45. Available at: http://www.accessmedicine.com/
content.aspx?aID=9097635. Accessed November 7, 2011.
10. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:15819.
11. Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 2007;120(11):S121.
12. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol
2009;29:28299.
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13. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in
patients hospitalized for worsening heart failure: the EVEREST outcome trial.
JAMA 2007;297(12):131931.
14. King JD, Rosner MH. Osmotic demyelination syndrome. Am J Med Sci 2010;
339(6):5617.